Colonoscopy screening is an effective intervention for identifying and removing precursor lesions for colorectal cancer (CRC). CRC has declined in incidence by 30% in the U.S. during the twenty years since adoption of colonoscopy screening that has enabled physicians to detect and remove polyps, the precursor lesion for CRC. While colonoscopy allows for observation of the endoscopic appearance of polyps by the practitioner and histological evaluation by pathologists, those measures of diagnostic scrutiny fall short of defining polyp properties that predict which lesions are most likely to transition through molecular events that commit a polyp to progress to cancer. Though the majority of CRC arises through malignant transformation of an adenomatous polyp, only 5% of those polyps progress to cancer. Currently, best practice protocols cannot discriminate between polyps containing molecular features leading to cancer from polyps that are likely to remain benign. In response to Provocative question #14, we seek to determine what the definable properties of CRC are, by comparing a polyp that has cancer from one that does not. Without a better understanding of the biological basis for polyp progression to cancer at the molecular level, physicians and patients approach decisions about treatment options without complete information about factors that predict the risk that polyps will transition to cancer. These studies propose to identify molecular features of polyps that differentiate the clinical behavior of given lesions so that optimal treatment opportunities can be determined for individual patients in the context of the probability that their polyps will progress to cancer. Recent studies utilizing molecular analysis f the genome, mRNA and micro RNA transcriptome or methylome (GTM) have attempted to depict the molecular features of carcinogenesis by studying independent polyps and cancer from different individuals. The first aim of this research will compare the molecular changes found in polyp tissue sets from individual patients with cancer adjacent polyps versus cancer-free polyps similar in terms of size, histology and degree of dysplasia. The second aim will refine the profiles of molecular features discovered in aim one by testing those refined profiles on a hundred sets of polyps in order to condense profile sets to affordable, accurate diagnostic panels of molecular progression. Finally, these profiles will be validated in a thousand sets of patient polyps to predict cancer progression risk in the clinical setting. The goals of this application are to develop an affordable, refined set of GTM events that answer fundamental questions about the molecular events that occur in polyps that have begun transformation to CRC compared to those that have not. These studies address a critical need to expand the base of knowledge upon which physicians and patients can make best case practice decisions for patients at risk for colorectal polyp transformation and progressive malignancy leading to invasive, metastatic colorectal cancer.